Rheumatoid arthritis (hereinafter also referred to as “RA”) mainly produces a symptom of multiple erosive arthritis, and rheumatoid arthritis is also unidentified systemic inflammatory disease affecting multiple organs. RA develops chronically while alternating between remission and exacerbation, causes the damage and deformation of joints if left untreated, and finally shows the dysfunction of motor organs. In some cases, RA is life-threatening. Therefore, RA patients suffer physically and mentally from heavy pain all their lives.
RA shows a wide variety of symptoms. For the diagnosis of RA, the diagnostic criteria by the American College of Rheumatology have been widely used. However, the RA onset is slow and usually takes several weeks to several months. The percentage positive of a rheumatoid factor, which is used as an objective index in the diagnostic criteria adopted by the American College of Rheumatology, is about 33% within three months and about 88% in twelve months and longer (Treatment, Vol. 73, No. 3, pp 23-27, in 1991), and a definite diagnosis of RA has not been achieved. Consequently, approaches to the diagnosis of rheumatoid arthritis have been made by detecting rheumatoid arthritis-associated IgM antibodies in patient sera that react with a recombinant antigen (See Japanese Laid-Open Patent Publication No. 513257/1998 (Tokukaihei 10-513257)).
Further, in the therapy for RA, therapeutic measures to be selected usually differ depending on a progressing course in the condition of RA pathema. Generally, in an early stage when a definite diagnosis cannot be given, non-steroidal anti-inflammatory drug (NSAID) is administered. In the case when the definite diagnosis can be given, disease modifying anti-rheumatic drugs (DMARD) is administered in addition to NSAID. Especially in the early stage of the RA onset, a definite diagnosis is difficult to be given. Under the present circumstances, discrimination from other rheumatoid diseases including collagen disease is carried out together with a careful observation of the progress while NSAID is administered. When symptoms progress further, steroid drug may be administered, and a medical therapy for the enhancement of pain relief is carried out together with a physical therapy and an orthotic therapy for the maintenance and recovery of joint function. Furthermore, when the joint damage causes inconvenience in a daily life, a surgical therapy may be carried out.
Aspects of arthritis and joint damage causing RA, particularly the pathological courses thereof, have been elucidated gradually through various research works. RA is induced by the concomitant participation of numerous causative factors including living environment and is then exacerbated progressively to the stage of apparent diseases; therefore, the interactive mechanism per se of such numerous factors should be elucidated for accurate characterization and appropriate therapeutic management of the disease. The prevalence of RA is not more than 1% on a global scale (New England Journal of Medicine, Vol. 322, p. 1277-1289, in 1990), but the frequency of the disease is about 8 times greater in the siblings of the patients with the disease (Cell, Vol. 85, p. 311-318, in 1996). Hence, it is predicted that a certain genetic factor may serve as one of the causative factors. Since an environment is regarded as one of the causative factors, previous knowledge of the RA onset possibility makes it possible to delay and prevent the RA onset by attentions to the diet, virus infection, stresses, etc. in daily life. Furthermore, an early diagnosis and a proper treatment in early stages can delay the course of RA and expect the improvement of prognosis.
One of immediate causes of RA is excessive inhibition of apoptosis. Regarding this, the following facts have been reported. In synovial cells of RA patients, apoptosis is induced in vitro by anti-Fas antibody (Arthritis and Rheumatism, Vol. 38, p. 485-491, in 1995). Further, administration of anti-Fas antibody to a human T-cell leukemia virus type I (HTLV-I) tax transgenic mouse as a model animal of RA inhibits edema of joints and arthritis (Journal of Clinical Investigation, Vol. 98, p. 271-278, in 1996); moreover, synovial cells of RA transplanted to the dorsum of a SCID mouse disappears by administration of anti-Fas antibody (Arthritis and Rheumatism, Vol. 41, p. 1251-1257, in 1998).
In International Patent Publication WO98/51791, the inventors of the present application have conducted the linkage analysis using microsatellite markers to RA patients and their siblings and specified three loci where causative genes of rheumatoid arthritis are located. The following causative genes have been identified:
(1) A causative gene of rheumatoid arthritis, which gene is located within ±1 centimorgan on a DNA sequence on human chromosome 1 to which the microsatellite markers D1S214 and/or D1S253 are hybridized.
(2) A causative gene of rheumatoid arthritis, which gene is located within ±1 centimorgan on a DNA sequence on human chromosome 8 to which the microsatellite marker D8S556 is hybridized.
(3) A causative gene of rheumatoid arthritis, which gene is located within ±1 centimorgan on a DNA sequence on human chromosome X to which the microsatellite markers DXS1001, DXS1047, DXS1205, DXS1227 and/or DXS1232 are hybridized.
Further, in Rheumatism, No. 39, No. 2, p. 444-445, the inventors of the present application have indicated death receptor 3 (hereinafter also referred to as “DR3”), which relates to the causative gene (1) with the markers D1S214 and D1S253, confirmed restriction fragment length polymorphism of DR3 between healthy subjects and RA patients, and suggested the possibility that DR3 may be the gene with relation to the disease sensitivity to RA.
An object of the present invention is to elucidate the relation between mutations of a genome in human DR3 and the RA onset or the RA onset possibility, and to provide a method of highly accurately diagnosing the RA onset or the RA onset possibility by using the mutations thereof. Another object of the present invention is to provide a diagnostic kit useful for detecting a genome having the mutations in DR3 responsible for RA or transcripts thereof. Still another object of the present invention is to provide a therapeutic method and remedies effective for the RA patients having the mutations in DR3.